Cavalieri E, Roth R, Grandjean C, Althoff J, Patil K, Liakus S, Marsh S
Chem Biol Interact. 1978 Jul;22(1):53-67. doi: 10.1016/0009-2797(78)90149-7.
The ability was tested of appropriate substituents of benzo[a]pyrene (BP) at C-6 to decrease or suppress the carcinogenic activity for these BP derivatives relative to the parent compound. 8-week-old female Swiss mice in 9 groups of 30 were treated on the back with 0.2 mumol of compound in acetone 4 times weekly for 20 weeks. The following compounds were administered: BP, 6-methylbenzo[a]pyrene (BP-6-CH3), 6-hydroxymethylbenzo[a]pyrene (BP-6-CH2OH), benzo[a]pyrene-6-carboxaldehyde (BP-6-CHO), benzo[a]pyrene-6-carboxylic acid, 6-methoxybenzo[a]pyrene, 6-acetoxybenzo[a]pyrene, 6-bromobenzo[a]pyrene, and 6-iodobenzo[a]pyrene. Two additional groups received BP or BP-6-CH3 twice weekly for 20 weeks at a total dose 25% of that above. In addition, the metabolism of selected 6-substituted BP derivatives was studied, using mouse skin homogenates in vitro and mouse skin in vivo. Only four compounds were carcinogenic; the order of potency was BP greater than BP-6-CH3 greater than BP-6-CH2OH and BP-6-CHO. The difference in carcinogenicity between BP-6-CH2OH and BP-6-CHO could not be assessed by this experiment. In a further tumorigenesis experiment the carcinogenicity of BP-6-CH2OH was compared to that of BP-6 CHO, BP-6-CH3 and 6-hydroxymethylbenzo[a]pyrere sulfate ester (BP-6-CH2OSO3Na) on mouse skin. 9-week-old female Swiss mice in groups of 28 were treated at three dose levels with 0.8, 0.2 and 0.05 mumol of compounds in dioxane--dimethyl sulfoxide (75 : 25) twice weekly for 40 weeks. After 40 experimental weeks BP-6-CH2OSO3Na proved to be a more potent carcinogen than BP-6-CH2OH, which, in turn was more active than BP-6-CHO. The greater carcinogenicity of BP-6-CH3 relative to BP-6-CH2OH and BP-6-CHO is confirmed, suggesting that BP-6-CH2OH is not a proximate carcinogenic metabolite for BP-6-CH3. Since BP-6-CHO is a weaker carcinogen than BP-6-CH2OH and is efficiently reduced metabolically to BP-6-CH2OH, the latter compound may be a common proximal carcinogenic metabolite. The stronger potency of BP-6-CH2OSO3Na, compared to its alcohol, suggests that an ester of BP-6-CH2OH might be the ultimate alkylating compound reacting with cellular nucleophiles.
测试了苯并[a]芘（BP）在C-6位的合适取代基降低或抑制这些BP衍生物相对于母体化合物致癌活性的能力。将9组每组30只8周龄雌性瑞士小鼠背部用丙酮中的0.2 μmol化合物每周处理4次，共20周。给予以下化合物：BP、6-甲基苯并[a]芘（BP-6-CH3）、6-羟甲基苯并[a]芘（BP-6-CH2OH）、苯并[a]芘-6-甲醛（BP-6-CHO）、苯并[a]芘-6-羧酸、6-甲氧基苯并[a]芘、6-乙酰氧基苯并[a]芘、6-溴苯并[a]芘和6-碘苯并[a]芘。另外两组每周用BP或BP-6-CH3处理2次，共20周，总剂量为上述剂量的25%。此外，使用体外小鼠皮肤匀浆和体内小鼠皮肤研究了选定的6-取代BP衍生物的代谢。只有四种化合物具有致癌性；效力顺序为BP＞BP-6-CH3＞BP-6-CH2OH和BP-6-CHO。本实验无法评估BP-6-CH2OH和BP-6-CHO之间致癌性的差异。在进一步的肿瘤发生实验中，将BP-6-CH2OH与BP-6-CHO、BP-6-CH3和6-羟甲基苯并[a]芘硫酸酯（BP-6-CH2OSO3Na）在小鼠皮肤上的致癌性进行了比较。将每组28只9周龄雌性瑞士小鼠用二氧六环-二甲基亚砜（75:25）中的0.8、0.2和0.05 μmol化合物每周处理2次，共40周。在40周的实验期后，BP-6-CH2OSO3Na被证明是比BP-6-CH2OH更强效的致癌物，而BP-6-CH2OH又比BP-6-CHO更具活性。BP-6-CH3相对于BP-6-CH2OH和BP-6-CHO的更强致癌性得到证实，表明BP-6-CH2OH不是BP-6-CH3的直接致癌代谢物。由于BP-6-CHO是比BP-6-CH2OH更弱的致癌物，并且能有效地代谢还原为BP-6-CH2OH，后一种化合物可能是常见的近端致癌代谢物。与醇相比，BP-6-CH2OSO3Na的效力更强，表明BP-6-CH2OH的酯可能是与细胞亲核试剂反应的最终烷基化化合物。
